A meta-analysis of unilateral axillary approach for robotic surgery compared with open surgery for differentiated thyroid carcinoma

Objective The Da Vinci Robot is the most advanced micro-control system in endoscopic surgical instruments and has gained a lot of valuable experience today. However, the technical feasibility and oncological safety of the robot over open surgery are still uncertain. This work is to systematically evaluate the efficacy of the unilateral axillary approach for robotic surgery compared to open surgery for differentiated thyroid carcinoma. Methods PubMed, Embase, Cochrane Library, and Web of Science databases were utilized to search for relevant literatures of robotic thyroid surgery using unilateral axillary approach compared to open thyroid surgery, and a meta-analysis was performed using RevMan software version 5.3. Statistical analysis was performed through Mantle-Haenszel and inverse variance methods. Results Twelve studies with a total of 2660 patients were included in the meta-analysis. The results showed that compared with the open group, the robotic group had a longer total thyroidectomy time, shorter hospital stay, less intraoperative bleeding, more postoperative drainage, fewer retrieved central lymph nodes, and higher cosmetic satisfaction (all P < 0.05). In contrast, temporary and permanent laryngeal recurrent nerve injury, temporary and permanent hypoparathyroidism or hypocalcemia, brachial plexus nerve injury, number of retrieved central lymph nodes, number of retrieved lymph nodes in the lateral cervical region, number of lymph node metastases in the lateral cervical region, hematoma, seroma, lymphatic leak, stimulated thyroglobulin (sTg) and unstimulated thyroglobulin (uTg), and the number and recurrence rate of patients with sTg <1ng/ml were not statistically different between the two groups (P > 0.05). Conclusions The unilateral axillary approach for robotic thyroid surgery may achieve outcomes similar to those of open surgery. Further validation is required in a prospective randomized controlled trial.


Introduction
Thyroid cancer is one of the most common endocrine-related cancers, and papillary and follicular carcinomas are collectively referred to as differentiated thyroid carcinomas (DTC).Compared to open thyroidectomy (OT), endoscopic thyroidectomy (ET) avoids neck scarring and has excellent cosmetic results, making it popular among patients.However, the scope of ET is affected by the limitations of rigid instruments.Robotic thyroidectomy (RT), which has the advantage of both "flexible" robotic arms and aesthetic appearance of the neck, is expected to overcome the shortcomings of ET and be gradually carried out all around the world.Currently, several approaches to RT have been used in clinical practice, including the unilateral axillary, bilateral axillary breast, transoral, and retroauricular approaches [1].Because of the small number of cases in each study, the efficacy cannot be objectively evaluated, and most of the existing meta-analyses have covered different approaches, resulting in high heterogeneity and affecting the credibility of conclusions [2][3][4].Therefore, this study intends to conduct a meta-analysis of RT versus OT in a single approach (unilateral axillary approach), and systematically evaluate their surgical efficacy as below.

Literature search
PubMed, Embase, Cochrane Library, and Web of Science databases were used for clinical literature research on the comparison of RT and OT.Keywords used were "robotic", "open", "conventional", "thyroidectomy", and "neoplasms".The retrieval time is from the establishment of the database to April 2023.The search strategy and PICOS strategy are shown in S1 Table.

Inclusion criteria
(1) randomized, non-randomized, case-control, cohort, and cross-sectional studies of RT and OT; (2) the surgical approach of RT is limited to the unilateral axillary approach; (3) postoperative pathology of patients confirmed to be DTC; and (4) at least one surgery-related outcome indicator can be provided.

Exclusion criteria
(1) history of neck surgery or radioactive iodine therapy; (2) repeated publication of literature, case reports, conference papers, expert comments, reviews, etc.; and (3) lack of original data and fruitless contact with authors.

Data extraction and literature quality evaluation
Two researchers independently screened the literature and extracted the relevant information.In case of disagreement, a third researcher was solicited to make the final decision.The extracted data included the following terms: basic information of the included studies (including the author, publication year, country, number of surgeries, sex, age, surgery procedure, follow-up time, study types, and quality scores) and 21 outcomes related to surgery (including temporary and permanent recurrent laryngeal nerve injury, temporary and permanent hypoparathyroidism or hypocalcemia, brachial plexus injury, number of retrieved central lymph nodes, number of central lymph node metastases, number of dissected lymph nodes in the lateral neck region, number of metastatic lymph nodes in the lateral neck region, time of total thyroidectomy, length of hospital stay, intraoperative blood loss, postoperative drainage, hematoma, seroma, lymphatic leakage, level of stimulated thyroglobulin (sTg) and unstimulated thyroglobulin (uTg), number of people with sTg <1ng/ml, recurrence rate, and cosmetic satisfaction rate).The criteria for temporary/permanent recurrent laryngeal nerve injury, temporary/permanent hypoparathyroidism, and hypocalcemia were determined according to the duration of each study.The rate of recurrent laryngeal nerve injury was calculated as follows: number of recurrent laryngeal nerve injuries/total number of recurrent laryngeal nerve exposure ×100%.The sTg levels were compared only in patients treated with radioactive iodine after total thyroidectomy.Cochrane criteria, Methodological Index for Non-Randomized Studies(MINORS), Newcastle-Ottawa scale(NOS), and Healthcare Research and Quality (AHRQ) were used to evaluate the quality of literature for randomized controlled studies, non-randomized controlled studies, cohort studies, and cross-sectional studies, respectively.

Statistical methods
RevMan software (version 5.3) was used for the meta-analysis.Statistical analysis was performed through Mantle-Haenszel and inverse variance methods.The risk ratio (RR) was used as the effect indicator for dichotomous variables, and the weighted mean difference (MD) or standardized mean difference was used for continuous variables.Random-effects models were used, with estimates and 95% confidence intervals (CIs) provided for all indicators.The test level for the meta-analysis was α = 0.05, and P < 0.05 was set as statistically significant.

Patient and public involvement
None.

Ethics approval statement
All analyses were based on previous published studies, thus no ethical approval and patient consent are required.

Literature retrieval results
After literature searching, 766 articles were initially retrieved, one article was added by tracing the original text through the references, 337 duplicate articles were removed, 396 were screened out by reading the titles and abstracts, 22 articles were excluded in strict accordance with the inclusion and exclusion criteria, and 12 studies were finally included in this metaanalysis.A flowchart of the search process is shown in Fig 1.

Discussion
Generally speaking, DTC tends to occur in women between 40 and 50 years of age; however, the current trend is becoming younger [15].Since the Da Vinci system was first used in thyroid surgery, different approaches have been proposed, which can be divided into two main approaches according to the operating direction: upward, bilateral axillo-breast approach, and unilateral axillary approach, as well as downward transoral and retroauricular approach [39].Among these approaches, the transoral and retroauricular approaches are more difficult to operate because of the opposite surgical field due to the downward direction of the operation.In particular, the retroauricular approach has a small operating space and is difficult to perform due to the contralateral thyroid gland, resulting in contralateral incisions for total resection.In addition, the bilateral axillo-breast approach is difficult in patients with thoracic deformities and prominent clavicle protrusions.This method requires the injection of carbon dioxide to maintain the operating space, which may lead to hypercapnia, subcutaneous emphysema, and even gas embolism.At the same time, a large range of subcutaneous tissue separation is required because of the four incisions, which have a great impact on the sensation of the breast and chest wall.Compared to the bilateral axillo-breast approach, the unilateral axillary approach has fewer incisions and a smaller flap-free area [21].
Owing to these advantages, an increasing number of patients choose the unilateral axillary approach.Based on the experience of 5000 cases of unilateral axillary RT, Kim et al. [40] believed that this surgical procedure has the potential to reduce perioperative complications and achieve better surgical and oncological outcomes.To date, several early systematic reviews and meta-analyses of RT versus OT [2][3][4][41][42][43][44][45][46][47][48] have been conducted, but the included studies were mixed with a variety of approaches, resulting in significant differences in the baseline characteristics of patients, high heterogeneity of results, and repeated inclusion of the same patient population, which affected the credibility of the results, which are shown in S2 Table .In this study, 12 included studies were strictly screened, and propensity score matching was used for four of them [11,13,14,16].It has been reported that propensity score matching can reduce selection bias, improve accuracy, and allow comparisons between different surgical procedures in nonrandomized retrospective studies [49,50].
Compared with OT, the safety of unilateral axillary approach RT was the most important.The results of this meta-analysis showed that intraoperative blood loss in the RT group was significantly reduced compared to that in the OT group (P < 0.05).This is because the robotic system is equipped with 3D high-definition lens equipment, which can enlarge the surgical field of vision by 10-15 times, enabling the surgeon to identify fine vessels more clearly, enabling more precise hemostasis, and reducing the occurrence of bleeding.
However, the RT group had more postoperative drainage, and the difference was statistically significant compared to the OT group.Tae [13] believes that the range of RT-separated flaps is approximately three times that of OT, including the lateral neck and anterior chest wall.As the exudate would increase with the increase in surgical scope, this may be the reason for the significant increase in drainage after RT.
In addition, the total resection times in the two groups were significantly different.The patients were divided into two subgroups according to the scope of lymph node dissection because of the high heterogeneity, showing low heterogeneity in both groups.Regardless of the dissection method, the operation time in the RT group was significantly longer than that in the OT group.This may be related to the RT operation process, which includes three steps: creating the operation space, instrument docking, and the surgical operation.During the operation, the dense tissue in the neck region and lack of natural space made it necessary to conduct free dissection of the skin flap first, and the complex instrument docking adjustments and difficulty in the treatment of the contralateral thyroid lobe led to longer RT time.Lee et al. [7] found that the operation time of RT was similar to that of OT if the cavity construction and docking times were excluded, and most surgeons generally believed that the total operation time might be gradually shortened with the proficiency of surgical techniques [51,52].
Another difference between the RT and OT groups was the length of the hospital stay.Some scholars believe that the discharge standards are that patients can walk freely after surgery, take drugs orally, tolerate pain, and have no surgically related complications [15].However, Lee et al. [5] suggested that the drainage tube should be safely pulled out after surgery before discharge.This study showed that hospital stay in the RT group was shorter than that in the OT group, which may indicate that RT is safe and reliable.The high heterogeneity may be related to the different definitions of discharge criteria by surgeons; thus, the results should be treated with caution.
Except for the obvious differences mentioned above, there were no significant differences in most complications between the RT and OT groups (P > 0.05), including temporary and permanent recurrent laryngeal nerve injury, temporary and permanent hypoparathyroidism or hypocalcemia, brachial plexus nerve injury, hematoma, seroma, or lymphatic leak.Unlike manually controlled lenses in ET, the robotic system has a more stable field of vision, alleviates the surgeon's sense of visual wobble and fatigue, and can better understand depth and distance.When dealing with the contralateral thyroid lobe, the camera could be rotated to ensure the surgical field of vision.For instance, if a deeper thyroid gland or forward protrusion of the trachea obstructs the operation, tilting the operating table contralateral upward by 10˚to 15c an better expose the contralateral tracheoesophageal groove.Combined with the highly flexible manipulator, the surgeon is able to finely dissect the posterior thyroid peritoneum during the surgical operation, which facilitates the identification and protection of the recurrent laryngeal nerve and parathyroid glands, and thus may achieve the same results as open surgery [53].
In addition to safety, complications, and other variables, the completeness of total thyroidectomy has been of great concern and can be estimated postoperatively by ultrasound, uTg, sTg levels and whole-body scan iodine uptake levels.Since Tg can only be produced by normal thyroid or differentiated thyroid cancer cells, the clinical detection of Tg is simple, sensitive, and less invasive, and is considered a reliable indicator to measure the amount of residual tissue after total thyroidectomy.It has been proven that sTg less than 1 ng/ml after radioiodine therapy is a good marker for complete thyroidectomy [54].Our study showed that the RT and OT groups had similar results with no statistical difference.
In addition, the number of cervical lymph node dissections is the main index for evaluating the thoroughness of surgery for DTC.Some studies have been conducted, but the high heterogeneity in most of them affects the reliability of the results [2,4,42].In this study, heterogeneity was significantly reduced by dividing central lymph node dissection into unilateral and bilateral subgroups.The results showed no significant difference in the number of lymph nodes dissected from the unilateral central region between the two groups.However, when dissecting both sides, fewer lymph nodes were obtained in the RT group than in the OT group, and this difference was statistically significant.On one hand, obstruction of the trachea may be the reason.In this case, the field of vision and manipulation of instruments were limited, especially in the dissection of the posterior lymph nodes of the contralateral recurrent laryngeal nerve.However, some early published studies included in this study may be in the early exploratory stage of this operation, and the patients enrolled in RT belong to the early stage of the disease, resulting in a small number of dissected lymph nodes.In the future, lymph nodes may be removed more thoroughly as the operator becomes more proficient.Next, the analysis results showed that there were no significant differences in the number of central lymph node metastases, the number of retrieved lymph nodes in the lateral cervical region, and the number of metastases between RT and OT.Additionally, the number of retrieved lymph nodes in each group was significantly greater than the number of metastases, indicating that RT met the requirements of oncology safety.Finally, There was no statistically significant difference in the postoperative recurrence rate between the two groups.However, Heaton et al. showed that higher lymph node yield in central and lateral neck dissections is associated with lower rates of papillary thyroid cancer recurrence in the central and lateral neck [55].Further studies are still needed.
Another noteworthy aspect was the cosmetic satisfaction rate after surgery for 3-6 months.The cosmetic satisfaction rate of patients in the RT group was significantly higher than that in the OT group.This is because the RT incision is in the axilla, which can be better hidden when the patient's upper limb is in the natural state, while the OT neck incision is obvious, especially in patients with a scar constitution.This was the original intention for the design of endoscopic thyroid surgery.
With the rapid development of RT technology, the Food and Drug Administration approved the latest Da Vinci SP system, namely the single-hole Da Vinci Robot for clinical use in 2018, in which all joints and endoscopes were inserted through a single-arm chamber with two control joints.This type of robot can perform more complex fine operations in a smaller anatomical area, which may further improve the operation of RT and simplify tedious regulatory steps.Some scholars have conducted preliminary explorations [56].
This study systematically evaluated the efficacy of unilateral axillary approach robotic thyroid surgery compared with open thyroid surgery in the treatment of DTC but still had the following limitations: (1) The current research did not register on PROSPERO, although we strictly followed the steps of systematic review, there may still be bias [57].(2) The 12 studies included in this meta-analysis were non-random or retrospective, and the criteria for temporary/permanent recurrent laryngeal nerve injury, temporary/permanent hypoparathyroidism, and hypocalcemia in each study may be different, although some studies have adopted the propensity score matching method, there may still exist bias.(3) The studies included originate all from the US and Korea, and some of these publications are authored by the same surgical teams, thus this meta-analysis may primarily reflect the experiences of a limited number of experts, potentially limiting the generalizability of the study results.(4) Most of the follow-up periods included in the literature were short.Since DTC is a relatively indolent malignant tumor, a longer follow-up period may be needed to evaluate the oncological safety of surgery.

Conclusion
Unilateral axillary robotic thyroid surgery may achieve results similar to those of traditional open surgery.Although the RT group had a longer total thyroidectomy time and more postoperative drainage, it showed shorter hospital stays, less intraoperative bleeding, less retrieved central lymph nodes, and higher cosmetic satisfaction, wherein all the differences were statistically significant (P < 0.05).To better understand RT, further validation in large prospective randomized controlled trials and long-term follow-up is required.